Aromatic chlorethylamines and their salts



Patented June 24, 1952 UNITED STATES PTENT OFFICE AROMATICCHLORETHYLAMIN ES AND THEIR SALTS William S. Gump, Upper Montclair, andEdward Joseph Nikawitz, Passaic, N. J assignors to The GivaudanCorporation, New York, N. Y., a corporation of New Jersey No Drawing.

( CsHsCI-I: CH- CH2) radical and a ---CH2CH2 halogen radical. Thecinnamyl radical may be substituted in the nucleus.

Specific members of our novel chemical compounds include the following:

N-(Z-chloroethyl)-N-cinnamyl ethylamine hydrochloride.

N-benzyl-N-(2-chloroethyl) cinnamylamine hydrochloride.

N-benzyl-N- (2-chloroethyl) -o-methyl cinnamylamine hydrochloride.N-p-methoxybenzyl-N- 2-chloroethyl) cinna mylamine hydrochloride.

In general, the novel salts of this invention may be prepared byreacting an equivalent amount of inorganic or organic acids with thecorresponding amines, preferably in some cases under anhydrous orsubstantially anhydrous conditions. The amines may be prepared byreacting the corresponding hydrohalides with at least an equivalentamount of alkaline material, such as, for example potassium carbonate.The hydrohalides may be prepared in general by reacting thebeta-alcohols of the amines with thionyl chloride or thionyl bromide.

The new salts of this invention are crystalline solids under usualatmospheric conditions and in general are soluble in alcohols andglycols, diflioulty soluble in water and insoluble in ether andhydrocarbons. The new amines are in general high boiling liquids,varying in color from water-white to yellow. They are not soluble inwater, but dissolve in ethyl alcohol, propylene glycol, and organicsolvents generally.

Our novel chemical compounds exhibit unexpected and desirable medicinalproperties, for example, as sympatholytic and adrenolytic agents. Fortherapeutic purposes these novel compounds may be administered orally orparenterally, and may be employed as tablets or in capsules or insolutions. Inaddition to their therapeutic properties our novelcompounds are useful in organic chemical synthesis.

While our invention comprehends salts of the amines set forth above andacids in general, we prefer to employ those acids having an ionizationconstant of at least about 1 10- at normal room temperature (about 250.). Examples of some suitable organic acids are picric, trichloro-Application October 29, 1949, Serial No. 124,481

acetic, oxalic and maleic acids. Examples of some suitable inorganicacids are hydrochloric, hydrobromic, sulfuric, phosphoric (firsthydrogen), perchloric, nitric and iodic acids.

In order to illustrate this invention more fully but without therebylimiting it, the following examples are given.

EXAMPLE 1 Preparation of N-(Z-chloroethyl)-N-cinnamyl ethylaminehydrochloride ((1) PREPARATION OF 2-(N-CINNAMYL-N-ETHYL) AMINOETHANOLFifty-three grams of cinnamyl chloride were dropped during one hour intograms of 2- ethylaminoethanol while the contents were stirred and heatedat 100 C. Heating at 100 C. was continued for 5 hours more. 200 cc. of a20% sodium hydroxide aqueous solution were added after the reactionmixture had cooled to room temperature. The amino alcohols wereextracted with 400 cc. of benzene and the benzene layer was washed with300 cc. of water, dried and filtered. After removal of the solvent, thedesired amino alcohol distilled as a yellow oil at 164-170" C. (4millimeters of mercury); yield 42.1 grams; n 1.5528; purity (determinedby potentiometric titration) 102%.

(b) PREPARATION OF N-(Z-CHLOROETHYL)-N-CIN- NAMYL ETHYLAMINEHYDROCHLORIDE 2(N cinnamyl N ethyl) 39.9 grams in 100 aminoethanol. cc.of chloroform Thionyl chloride 26 grams in 100 cc.

of chloroform The thionyl chloride was dropped during 2 hours into theamino alcohol under stirring and cooling in an ice bath. After standingfor a few hours at room temperature, the solvent was removed bydistillation. The solid residue was recrystallized from 100 cc. of ethylalcohol and 300 cc. of isopropyl ether and again from 100 cc. of ethylalcohol and 200 cc. of isopropyl ether. 34 grams of white crystals witha M. P. of l50- 152 C. were obtained Anal. Calcd. for C13H19NC122 01ion, 13.6; C1 total, 27.3. Found: Cl ion, 13.7; C1 total, 27.3.

EXAMPLE 2 Preparation of N-benzyZ-N-(Z-chloroethyl) cinnamylaminehydrochloride (0) PREPARATION OF 2-(N-BENZYL-N-CINNAMYL) AMINOETHANOLForty-six grams of cinnamyl chloride and grams of 2-benzylaminoethanolwere brought to reaction following the procedure described in Example1a. By distillation at 4 millimeters of mercury pressure 54.4 grams ofthe desired amino alcohol was obtained as a yellow oil; B. P. 217- 225C. (4 millimeters); 11 1.5878; purity 101% (by potentiometrictitration).

(b) PREPARATION OF N-BENZYL-N-(2-cIILoRoETrL YL) CINNAMYLAMINEHYDROCHLORIDE .Fifty-two grams of the above amino alcohol (Example 2a)dissolved in 100 cc. of chloroform and 27 grams of thionyl chloride in 1cc. of chloroform were brought to reaction as described in Example lb.The residue obtained after removal of the solvent was resinous.Consecutive crystallizations using: (1) 100 cc. of ethyl alcohol and 600cc. of isopropyl ether, (2) 100 cc. of ethyl alcohol and 300 cc. ofisopropyl ether, (3) 200 cc. of ethyl alcohol and 500 cc. of isopropylether, and finally 1) 200 cc. of ethyl alcohol and 500 cc. of isopropylether yielded 17.9 grams of the desired compound in the form of whitecrystals with a M. P. of l50-l52 C.

Anal. Calcd. for C'mHnNClz: Cl ion, 11.0; Cl total, 22.0; Found: Cl ion,11.1; C1 total, 22.1.

EXAMPLE 3 Preparation of N-benzyZ-N-(Z-chloroethyi)-omethylcinnamylamine hydrochloride (a) PREPARATION OF O-METHY L CINNAMYLBROMIDE A Grignard solution was prepared in the usual manner from 72grams of magnesium and 500 grams of o-bromo-toluene dissolved in 900 cc.of absolute ethyl ether. 170 grams of acrolein dissolved in 600 cc. ofabsolute ethyl ether were added during one hour to the stirred Grignardsolution while the contents were cooled to C. to 0 C; Stirring at thistemperature was continued for 2 hours and finally for 12 hours at roomtemperature.

The formed addition product was decomposed by pouring it slowly onto amixture of ice, water and hydrochloric acid. The ether layer containingthe reaction product was washed twice with a 10% sodium bicarbonateaqueous solution and dried with anhydrous sodium sulfate. Afterfiltration and removal of the solvent, 143 grams of o-tolyl allylcarbinol were obtained by distillation; B. P. 115123 C. (5 millimetersof mercury); 11, 1.5 162. Considerable amounts of high boiling, resinoussubstances were also formed.

o-Tolyl allyl carbinol is not very stable and polymerizes on standing.

Seventy grams of o-tolyl allyl carbinol were slowly added under stirringto 460 grams of acetic acid containing 30% (by weight) of hydrogenbromide. After being stirred for 15 minutes, the reaction product waspoured into 3 liters of water and extracted with 500 cc. of ether. Theether solution was Washed twice with a 10% sodium bicarbonate aqueoussolution, then with water alone, and then dried with anhydrous sodiumsulfate. After filtration and removal of the solvent, 90.7 grams ofo-methyl cinnamyl bromide distilling at 135-145 C. (4 millimeters ofmercury) were obtained. This compound is not very stable and somehydrogen bromide is formed on standing.

(1)) PREPARATION OF 2-(N-BENZYL-N-o-METHYL CINNAMYL) AMINOETHANOLForty-two grams of o-methyl cinnamyl bromide were dropped during onehour into sixtytwo grams of 2-benzyl aminoethanol and heated to C. underagitation. Heating at this temperature and stirring was continued for 3hours. After the mixture had cooled to room temperature 200 cc. of a 20%sodium hydroxide aqueous solution were added and the amino alcoholsextracted with 200 cc. of benzene. The benzene layer was washed with 300cc. of water and dried with anhydrous sodium sulfate. After removal ofthe solvent, 23 grams of the desired amino alcohol distilled as a yellowoil at 222-2515 C. (4 millimeters of mercury); n 1.4789; purity 99(determined by potentiometric titration).

(o) PREPARATION OF N BENZYL N (2-CHLORO- ETHYL) 0 METHYL CINNAMYLAMINEHYDRO- CHLORIDE Twenty-two grams of the above amino alcohol (Example 3b)dissolved in 100 cc. of chloroform and 12 grams of thionyl chloride in50 cc. of chloroform were brought to reaction as described in Example112. After allowing the reaction mixture to remain at room temperaturefor 12 hours, the solvent was removed by distillation. The remainingresin was obtained in form of white crystals (9.5 grams) with a M. P. of154456 C. by consecutive crystallizations using (1) 100 cc. of alcoholand 1,000 cc. of ether, (2) 80 cc. of alcohol and 500 cc. of ether, andfinally (3') Slice. of alcohol and 60 cc. of ether.

Anal. Calcd. for Crel-IzsNClz: Cl ion, 1016'; C1 total, 21.1. Found: Clion, 10.3; C1 total, 21.1.

EXAMPLE 4 Preparation of N-p-methomybenzyZ-N(2- chloroethyl)cinnamylamine hydrochloride (a) PREPARATION OF 2-pMETHOXYBENZYLAMINO-ETHANOL Ninety-five grams of p-methoxybenzyl chloride were droppedduring one hour into 220 gramscf Z-aminoethanol while the contents werestirred and heated at C. Heating at 110 C. was continued for 3 hours.After cooling to 80 C. a solution of 25 grams of sodium hydroxide in 40cc. of water and 400 cc. of alcohol were added to the reaction mixture.The sodium chloride was precipitated nearly completely by cooling to 0C. and was filtered off. The solvent was removed by distillation in lowvacuum. 70.9 grams of 2-p-methoxybenzylaminoethanol with a purity of99.2% (as measured by potentiometric titration) distilled as a yellowoil at 175-180 C. (4 millimeters of mercury).

(b) PREPARATION OF 2-(N-p-\lETHOXYBENZYL-N- CINNAMYL)AMINOETHANOL Thirtyone grams of cinnaznyl chloride were dropped during 2 hours into '70grams of 2 pmethoxybenzylaminoethanol while the contents were stirredand heated at 110 C. The reaction was completed on heating the mixturerors hours at 110 C. and finally for 10 minutes at C. After allowing themixture to cool to room temperature 200 cc. of a 20% sodium hydroxidesolution were added and the amino alcohols were extracted with 300 cc.of benzene. The benzene layer was washed with 400 cc. of water and driedwith anhydrous sodium sulfate. After removal of the solvent 36.2 gramsof the desired amino alcohol with a B P of 245-255 C. (1' millimeters ofmercury) and'a purity of 99.4% (as measured by potentio'metrictitration) were obtained by vacuum distillation.

(c) PREPARATION OF N-p-METHOXYBENZYL-N-(Z- glfigROETHYL) CINNAMYLAMINEHYDROCHLO- I'wenty-nine and seven tenths grams of 2-(N- pmethoxybenzyl-N cinnamyl) aminoethanol dissolved in 100 cc. ofchloroform were brought to reaction with a solution of 15 grams ofthionyl chloride in 100 cc. of chloroform following the proceduredescribed in Example 1b. A resin was obtained which became crystallineafter being kept in absolute ether for two months. Recrystallizationfrom 100 cc. of ethyl alcohol and 700 cc. of ether and from 100 cc. ofalcohol and 600 cc. of ether yielded 7.5 grams of white crystals; M. P.134-l36 C.

Anal. Calcd. for CmHzsNOClz: Cl ion, 10.1; C1

total, 20.2. Found: C1 ion, 10.4; C1 total, 20.2. The foregoingillustrates the practice of this invention, which however, is not to belimited thereby but is to be construed as broadly as permissible in viewof the prior art and limited solely by the appended claims.

We claim: 1. Compounds having the general formula:

omomol 6 wherein R1 is a member selected from the group consisting ofCZH benzyl and methoxybenzyl and R2 is a member selected from the groupconsisting of cinnamyl and methyl cinnamyl; and salts thereof withacids.

2. N 2-ch1oroethy1) N-cinnamyl ethylamine hydrochloride.

3. N-benzyl-N-(2-chloroethyl) cinnamylamine hydrochloride.

4. N benzyl N (2-chloroethyl) o methyl cinnamylamine hydrochloride.

5. N p-methoxybenzyl N (2 chloroethyl) cinnamylamine hydrochloride.

WILLIAM S. GUMP. EDWARD JOSEPH NIKAWITZ.

REFERENCES CITED The following references are of record in the file ofthis patent:

Nlckerson et a1.: Fed. Proc., vol. 5. pp. 194-195 (1946).

Goldin et a1.: J. Pharm. Exp. Therapy, vol. 94. p. 256 (1948).

Hunt: J. Pharm. Exp. Therapy, vol. 95. pp. 177-184 (1949).

1. COMPOUNDS HAVING THE GENERAL FORMULA: